Four NONOate compounds with different rates of nitric oxide generation have been used in both copper(II) sulfate and ABAP-mediated oxidation to assess the effect of nitric oxide production rate on the inhibition of LDL oxidation. During copper-mediated oxidation, PAPA and spermine NONOate were more efficient in inhibiting LDL oxidation than MHAMA and DETA NONOate. This indicates a biphasic relationship between the rate of nitric oxide production and the efficacy of the antioxidant activity of nitric oxide. This relationship was also demonstrated during ABAP-mediated oxidation. However in this case, DETA was more effective than PAPA at inhibiting oxidation. In the conditions used in this study, copper-mediated oxidation occurred 2-3 times more rapidly than ABAP-mediated oxidation. This suggests that the effectiveness of a particular nitric oxide-donating compound depends on the rate of nitric oxide release and the rate of oxidation. Preliminary results indicate that RAW 246.7 macrophage-mediated LDL, which occurs very slowly in vitro, is maximally inhibited by the slower releasing nitric oxide donors. The inhibition of `-tocopherol depletion during ABAP-mediated oxidation was inhibited by spermine and PAPA NONOate, but not MHAMA and DETA NONOate. The observation that DETA NONOate is able to inhibit both TBARS formation and the increase in REM, but not inhibit `-tocopherol depletion suggests that: 1) Inhibition of LDL oxidation is not a result of trapping the initiating ABAP peroxyl radicals. 2) DETA NONOate generates a low steady-state concentration of nitric oxide that is unable to complete with `-tocopherol as a peroxyl radical scavenger. However, even under these conditions, nitric oxide is still a potent inhibitor of LDL oxidation. The production of nitric oxide by the vascular endothelium represents a continuous source of antioxidant, which may suppress oxidative reactions in the vasculature.